Abstract Bmi-1 and the other Polycomb Group (PcG) genes are important epigenetic regulators of cell survival. In spite of this realization the possibility that they may play a role maintaining epidermal keratinocyte survival has not been considered. This is likely because this area is now at the forefront of discovery since the importance of these proteins was only recently appreciated. Our preliminary studies show that Bmi-1 is present in epidermis and that elevated Bmi-1 promotes keratinocyte proliferation and survival. We also show that Bmi-1 is elevated in diseases such as psoriasis and cancer, suggesting a role in the genesis of these disorders. We have created an animal model that develops a thickened hyperproliferative epidermis in response to Bmi-1 - a finding that suggests a functional role in epidermal physiology. Specific Aim 1 is designed to assess the impact of Bmi-1 in epidermal keratinocyte proliferation and survival and to study the chromatin modification events associated with Bmi-1 dependent suppression of involucrin gene expression. Specific Aim 2 is designed to characterize the anti-apoptosis effect of Bmi-1. Specific Aim 3 will identify Bmi-1 domain(s) that are responsible for the physiological changes in apoptosis, cell proliferation and gene expression. Specific Aim 4 utilizes transgenic mice which express Bmi-1 in epidermis to assess the in vivo role of this epigenetic regulator. We believe that these studies are innovative and high impact because they will change the classical dogma regarding the role of Bmi-1 and other PcG genes in tissues. NARRATIVE: The Bmi-1 Polycomb Group (PcG) gene is an important epigenetic regulator that enhances stem cell survival. However, a role in epidermis has not been studied. We show that Bmi-1 is expressed in epidermis, promotes cell cycle progression, inhibits apoptosis, has non-stem cell functions, drives hyperproliferation in mouse epidermis, and is likely to be involved in the genesis of hyperproliferative skin disease. These studies argue that Bmi-1 has a physiologically important role in epidermis. These studies are innovative and high impact because they will change the classical dogma regarding the role of PcG genes in tissues.